Kidney transplantation is considered the best therapeutic option for patients affected by end-stage renal failure, but this possibility is limited by a shortage of donors. Living-donor kidney transplantation (LDKD) is a valuable option, frequently limited by immunological incompatibility between donor and recipient. This review will consider the possibility of performing living-donor kidney donation in the case of AB0 blood group incompatibility and the progress that has been made in this field. Kidney-paired donation is one possibility. This technique is the best option if there are numerous available pairs. This approach is possible because of national and international registries. The more diffuse technique is the desensitization of the recipients. Desensitization may be achieved in several ways, which are extensively discussed in this review. Recently, some published studies documented the possibility of enzymatically converting the A or B groups from the cells of the donor to the O group. This approach is only in a nascent stage but may represent the future, eventually associated with mild desensitization.

According United States renal data system the morbidity rate for chronic kidney disease (CKD) is 2.5 times than patients not affected by CKD and the mortality rate is 144.9 per 1000 persons-years. The gut microbiota is involved in uremic toxins (UTs) production. This fact was demonstrated by experiments in rats, which revealed better survival in CKD rats that were deprived of the gut microbiota. In men, UT levels are low in CKD patients without a colon. Diet may affect the gut microbiota through food additives such as prebiotics, probiotics and post biotics. Conservation processes and food processing may also affect the gut microbiota. Other factors are food quantity and composition. The gut microbiota may be the cause of UTs production and accumulation in the blood. Additionally, there is interplay among different organs such as liver, kidney and gut. Several theories have been formulated to justify the interplay between the metabolic dysfunctions. In particular, the increase of species such as Eggerthelia lenta, Fusobacterium nucleatum and Alistipes shahii leads to an increase of the aromatic amino acids degradation, and secondary bile acids and trimethyamine oxide biosynthesis in the intestine. This fact determines an increase of the levels of UT precursors such as indole, p-cresol, phenol, phenylacetaleyde, benzoic acid and trimethylamine. Recent studies document the following. The human microbiome project revealed that the gut microbiota may play an important role in both human health and diseases, including kidney disease. Recently, several studies have shown a strict correlation between the gut microbiota and CKD. Probiotics, prebiotics and synbiotics are possible therapies. Probiotics are living microorganisms that, consumed in adequate quantities, are beneficial for the patient, and act on the intestinal microbiome equilibrium. Lactobacilli and Bifidobacteria are common examples of probiotics. Prebiotics are generally fibers not absorbed by the gut, representing a selective nutrient for the microbiome already present in the gut, which favors their growth and activity. Inulin, fructo-oligosaccharides and other fibers are examples of prebiotics. The association and synergism between probiotics and prebiotics is symbiotic.

Kidney transplantation for patients affected by end stage renal failure is considered the best therapeutic option, but this possibility is limited by deceased donor shortage. Living donor kidney transplantation (LDKD) is a valuable option, frequently limited by immunological incompatibility between donor and recipient. This review will consider the to date possibility of performing living donor kidney donation in the case of AB0 blood group incompatibility and the progresses that have been made in this field. Kidney paired donation is one possibility. Such technique offers the best possibility if the number of pairs available is wide. This is possible by performing national and also international registries. The technique more diffuse is the desensitization of the recipients. Desensitization may be obtained by several ways that are extensively treated in this review. In the recent period some published studies document the possibility to enzymatically convert A or B group from the cells of the donor to 0 group. This possibility is only on the beginning, but may represent the future eventually associated to a mild desensitization.

In recent years, the use of new biomarkers in different phases of the diagnosis and treatment of several diseases has allowed substantial improvement in clinical practice. The use of donor-derived cell-free DNA (dd-cfDNA) in organ transplantation has led to significant progress in the treatment of post-transplant outcomes, particularly after kidney transplantation. In addition, the use of dd-cfDNA in organ transplantation has led to significant advancements in post-transplant outcome monitoring. The aim of this study is to review many of the recent studies on the use of this biomarker and to evaluate its most relevant advantages and limitations. dd-cfDNA is released from several types of cells of the transplanted organ, most often from endothelial cells and this happens in the case of organ damage, most often rejection. Its presence in the bloodstream of the recipients is an important sign of graft damage; its principal advantage is in the avoidance of invasive tools such as renal biopsy. Additionally, several studies reported that the finding of dd-cfDNA in the serum may precede histological abnormalities; its utility in the diagnosis of subclinical rejection is extremely important. Among the principal limitations of this tool are the difficulty in distinguishing different forms of graft damage. According to several studies this tool has several limitations in diagnosing T-cell mediated rejection. In addition, particular care should be taken in distinguishing dd-cfDNA from recipient-derived cfDNA.

Background. Recurrent primary glomerulonephritis is a frequent and severe disease that represents the second or third leading cause of graft loss. Objective. The purpose of this study is to address the rates of recurrence for all types of glomerulonephritis, detailing their characteristics and the treatments adopted. Methods: The authors collected the main studies and meta-analyses published on PubMed. In addition, the main clinical trials ongoing on the topic were collected. The results highlighted the different frequency of recurrence in relation to the glomerulonephritis considered, assessing the different characteristics and the different treatments adopted. In conclusion, this review confirms the severity of this disease. The treatment possibilities differ among glomerulonephritis variants. Frequently, a pre-transplant period should be distinguished from a peri-transplant period and a post-transplant period. Finally, new drugs are being discovered to treat recurrent glomerulonephritis and several ongoing trials are also discussed. Some of them have shown important results already.

In the application of the digital twin model of the digging face, the data transmission will be transmitted to the remote control platform through the physical hardware via the gateway, and this cross-system and cross-software data transmission mode will inevitably generate the transmission delay, which leads to a certain spatial-temporal deviation between the virtual scene of the remote control platform and the physical digging site. In this paper, by analyzing the operation process of roadheading equipment, a state evolution dynamics model construction method for roadheading equipment is proposed, which includes three stages, namely, discretization of positional state based on cutting path planning, event-driven construction of cutting state evolution map of roadheading equipment and real-time data-driven dynamics evolution of roadheading equipment, and the construction of roadheading equipment state evolution dynamics model provides the best solution for the roadheading equipment. The construction of the model provides theoretical basis and technical support for the construction and alignment of the digital twin multidimensional model of the roadheading equipment.

Cancer is the second cause of death in kidney transplant patients in most Western countries. The excess risk of cancer after kidney transplantation is two to three times higher than in the age and sex matched general population. Once cancer develops, the outcome is generally poor, particularly for melanoma, renal cell carcinoma and post-transplant lymphoproliferative disorder. A multidisciplinary approach for screening, prevention, diagnosis and treatment of neoplastic disease after kidney transplantation is necessary.

The Human Microbiome Project, Earth Microbiome Project, and next-generation sequencing have advanced novel genome association, host genetic linkages, and pathogen identification. The microbiome is the sum of the microbes, their genetic information, and their ecological niche. This study will describe how millions of bacteria in the gut affect the human body in health and disease. The gut microbiome changes in relation with age, with an increase in Bacteroidetes and Firmicutes . Host and environmental factors affecting the gut microbiome are diet, drugs, age, smoking, exercise, and host genetics. In addition, changes in the gut microbiome may affect the local gut immune system and systemic immune system. In this study, we discuss how the microbiome may affect the metabolism of healthy subjects or may affect the pathogenesis of metabolism-generating metabolic diseases. Due to the high number of publications on the argument, from a methodologically point of view, we decided to select the best papers published in referred journals in the last 3 years. Then we selected the previously published papers. The major goals of our study were to elucidate which microbiome and by which pathways are related to healthy and disease conditions.

Sodium glucose cotransporter type 2 inhibitors are a new class of drugs that act on the cardiovascular system, kidneys and metabolism in a multiple ways. Indeed, even though their principal action involves the transport of sodium and glucose in the convoluted distal tubule, they have multiple actions, such as antifibrotic and endothelial protective effects. Their principal mechanism consists of the loss of sodium and glucose. Therefore, they affect blood pressure and glucose metabolism. Their first use was in the diabetic general population; later, some studies documented their activity in the nondiabetic general population and in heart failure in chronic kidney disease patients. Only in recent years have several small studies documented the efficacy of these drugs in diabetic and nondiabetic kidney transplant patients; relatively large studies are rare, very recent, and open new routes for the development of these drugs.

Gut microbiota is often modified after kidney transplantation. This principally happens in the first period after transplantation. Antibiotics and, most of all, immunosuppressive drugs are the main responsible. The relationship between immunosuppressive drugs and the gut microbiota is bilateral. From one side immunosuppressive drugs modify the gut microbiota, often generating dysbiosis; from the other side microbiota may interfere with the immunosuppressant pharmacokinetics, producing products more or less active with respect to the original drug. These phenomena have influence over the graft outcomes and clinical consequences as rejections, infections, diarrhea may be caused by the dysbiotic condition. Corticosteroids, calcineurin inhibitors such as tacrolimus and cyclosporine, mycophenolate mofetil and mTOR inhibitors are the immunosuppressive drugs whose effect on the gut microbiota is better known. In contrast is well known how the gut microbiota may interfere with glucocorticoids, which may be transformed into androgens. Tacrolimus may be transformed by microbiota into a product called M1 that is 15-fold less active with respect to tacrolimus. The pro-drug mycophenolate mofetil is normally transformed in mycophenolic acid that according the presence or not of microbes producing the enzyme glucuronidase, may be transformed into the inactive product.

Precision medicine is mainly based on reliable and noninvasive biomarkers. The aim of this review was to describe the newest biomarkers in the field of kidney transplantation and kidney rejection, one of the most common and severe complications. The standard tools used to identify acute rejection largely result in errors and have many drawbacks. In recent years, new and reliable biomarkers have been identified. These methods avoid risks, are noninvasive, and are able to detect rejection even in cases in which acute rejection is clinically asymptomatic and not otherwise identifiable, which is a frequent occurrence. In recent years, several biomarkers have been identified. Very recently, new relevant biomarkers with high positive predictive value and low negative predictive value have been identified. These are the donor-derived cell-free DNA found in the recipient, the gene expression profile of the donor found in the recipient, and the urinary cytokines that are modified in the graft tissue. The aim of this study was to identify the most recent findings in the literature on this topic and to describe the utility and possible limitations of such new biomarkers for kidney rejection.

Infections remain a common complication of solid-organ transplantation and are a major factor of morbidity and mortality in renal transplant recipients. The incidence of infection in renal transplant patients is directly related to the net immunosuppressive effect achieved and the duration of the administration of immunosuppressive therapy. The major types of infections can be categorized according to the time post-transplant during which they occur: in the first month after transplantation post-surgical bacterial infections and in the period from one to four months post-transplant opportunistic infections, overall cytomegalovirus; late infections, beyond 6-12 months, are community-acquired infections. Opportunistic infections (like Pneumocystis carini, Listeria monocytogenes, and Aspergillus fumigatus) most frequently occur in the first 12 months post-transplant and can be modulated by prior exposures and the use of prophylaxis.

Recently, new findings have been clarified concerning both pathogenesis and treatment of IgA nephritis. The four hits theory has been confirmed but several genetic wide association studies have allowed finding several genes connected with the pathogenesis of the disease. All these new genes apply to each of the four hits. Additionally, new discoveries concerning the microbiota and its connection with immune system and IgA generation have allowed finding out the role of the mucosa in IgA nephropathy pathogenesis. The IgA treatment is also changed included the future possibilities. The treatment of the chronic kidney disease, associated with the nephropathy, is mandatory, since the beginning of the disease. The classical immunosuppressive agents have poor effect. The corticosteroids remain an important cornerstone in any phase of the disease. More effect is related to the treatment of B cells and plasma cells. In particular, in very recent studies have been documented the efficacy of anti B cell-activating factor and anti A proliferation-inducing ligand agents. Most of these studies are to date in phase II/III. Finally, new agents targeting complement are arising. These agents also are still in randomized trials and act principally in hit 4 where the immunocomplexes in the mesangium activate the different pathways of the complement cascade.

Recently, new interesting and important novel biomarkers have allowed the evidence based medicine to move to a new field called precision medicine. In particular, this apply to organ transplantation and to the diagnosis of rejection. Among these novel biomarkers are the study of donor-derived cell-free DNA when present in the blood of the recipients, the study of gene expression profiling again in the recipient, and the study of several urinary cytokines. All these novel biomarkers have several advantages over the old biomarkers. Indeed, they are non-invasive, are able to detect renal damage before the appearance of histological abnormalities, and are able to distinguish antibody-mediated rejection from cell-mediated rejection. The aim of this study is to identify the most recent findings on these biomarkers and to describe their utility and their limitations in particular in the field of kidney acute rejection.

One of the major challenges in developing programs for kidney transplantation is represented by the presence of antibodies targeting the HLA of the donor in the recipients and, in particular cases, the incompatibility of the ABO blood groups among donor and recipient for living donors [...]

The presence in a recipient of antibodies directed against donor-specific antigens represents a major obstacle to transplantation. Removal of these antibodies represents a challenge for physicians dealing with kidney transplantation. Several strategies, techniques, and old and new drugs are currently used for desensitizing these patients. Desensitization may either occur before transplantation, at the time of transplantation, or after transplantation according to whether physicians are dealing with living or deceased donors. Different techniques may be used to reveal the presence of antibodies in the recipients; each technique has different sensitivities and specificities, and different advantages and drawbacks. The targets of the drugs used to desensitize are B cells, plasma cells, the antibodies themselves, and, finally, the complement that is the final actor causing tissue disruption. B cells are relatively easy to target; targeting the plasma cell is more difficult. Indeed, several new drugs are also used in randomized trials to defeat plasma cells. Antibodies may be removed easily, but their removal is often followed by antibody rebound. The complement is not easy to defeat and new drugs are currently used for this aim. Overall, despite difficulties, desensitization is currently possible in many cases, to obtain a safe and successful transplantation.

ARTICLES DISCUSSED:Schmidt, D. et al. TBase - An integrated electronic health record and research database for kidney transplant recipients. Journal of Visualized Experiments. (170), e61971 (2021). Duettmann, W. et al. Digital home-monitoring of patients after kidney transplantation: The MACCS platform. Journal of Visualized Experiments. (170), e61899 (2021). Lim, S. J. et al. Robot-assisted kidney transplantation. Journal of Visualized Experiments. (173), e62220 (2021). You, H. et al. A rat orthotopic renal transplantation model for renal allograft rejection. Journal of Visualized Experiments. (180), e63464 (2022). Yin, D. et al. Modified surgical technique for kidney transplantation in mice. Journal of Visualized Experiments. (185), e63434 (2022).

Medicine has evolved from the so-called experience-based medicine to evidence-based medicine, which is now evolving into precision-based medicine [...]

Several diseases are related to complement involvement. In particular, its role is essential for the pathogenesis of several renal disease. On the other hand, the complement role may also be protective, and this possibility should be well known when managing complement inhibitors. Complement inhibitors are relatively newly discovered therapies that are essential in some diseases, and in others improve the efficacy of the already known therapeutic measures that represent the standard of care. In the case of glomerular diseases, complement plays a role in almost all diseases. In some diseases, complement abnormalities represent the prevailing factor in the pathogenesis. In such diseases, complement inhibition represents an essential therapy. In other diseases, complement plays an important role, but other factors are involved in the pathogenesis. Clearly, in these diseases, complement inhibition represents a therapy that could be added to the standard of care therapy, according to the physician’s judgement. Examples of these diseases are lupus nephritis, thrombotic microangiopathy when associated to some cases of lupus nephritis, and IgA nephropathy. The latter is one of the first primary glomerulonephritides in which a relevant role of complement is documented. These three diseases are the object of this brief review. Particular concern should be given to ongoing clinical trials. Indeed, many of these anti-complement therapies are still in different phases of clinical trials. Finally, particular concern must be ascribed to the problem of associating these emerging therapies to already existing and proven treatments.

ABSTRACTIgA nephropathy (IgAN) is a progressive form of kidney disease defined by glomerular deposition of IgA. We performed a genome-wide association study involving 10,146 kidney biopsy-diagnosed IgAN cases and 28,751 matched controls across 17 international cohorts. We defined 30 independent genome-wide significant risk loci jointly explaining 11% of disease risk. A total of 16 loci were novel, including TNFSF4, REL, CD28, CXCL8/PF4V1, LY86, LYN, ANXA3, TNFSF8/15, REEP3, ZMIZ1, RELA, ETS1, IGH, IRF8, TNFRSF13B and FCAR. The SNP-based heritability of IgAN was estimated at 23%. We observed a positive genetic correlation between IgAN and total serum IgA levels, allergy, tonsillectomy, and several infections, and a negative correlation with inflammatory bowel disease. All significant non-HLA loci shared with serum IgA levels had a concordant effect on the risk of IgAN. Moreover, IgAN loci were globally enriched in gene orthologs causing abnormal IgA levels when genetically manipulated in mice. The explained heritability was enriched in the regulatory elements of cells from the immune and hematopoietic systems and intestinal mucosa, providing support for the pathogenic role of extra-renal tissues. The polygenic risk of IgAN was associated with early disease onset, increased lifetime risk of kidney failure, as well as hematuria and several other traits in a phenome-wide association study of 590,515 individuals. In the comprehensive functional annotation analysis of candidate causal genes across genome-wide significant loci, we observed the convergence of biological candidates on a common set of inflammatory signaling pathways and cytokine ligand-receptor pairs, prioritizing potential new drug targets.